Abstract
"Activation" of integrins is involved in the dramatic transition of leukocytes and platelets from suspension to adhesion. The integrin alpha v beta 3 is not known to take part in this sort of transition, even though it shares its beta subunit with alpha IIb beta 3, the activable integrin on platelets. In the context of a constitutively adhered cell, changes in activation state may be more subtle in their effects, but nonetheless important in regulating cell behavior. We hypothesized that alpha v beta 3 can undergo conformational changes analogous to those associated with alpha IIb beta 3 activation. Accordingly, we examined alpha v beta 3 on the surface of M21 cells (a human melanoma cell line) and found that, like alpha IIb beta 3, it can undergo conformational changes upon binding of a ligand analog and can be activated for ligand binding and migration by a monoclonal antibody directed against beta 3. Modulation of the binding of this activating antibody, AP5, ligand binding, and antibody-mediated activation all are associated with a discrete cation-binding site shared in both alpha IIb beta 3 and alpha v beta 3. Based on a measured Ki, this site has an apparent Kd for calcium of approximately 20 microM. At physiological levels of calcium, about 40% of the total alpha v beta 3 on a cell's surface is in a conformation detected by AP5. The data suggest a model for both alpha v beta 3 and alpha IIb beta 3 function in which the molecule can exist in either of (at least) two conformational states, one stabilized either by AP5 or ligand binding, refractory to calcium binding, and enhanced for ligand recognition, the other stabilized by calcium binding and refractory to AP5 and ligand binding. Functional analysis suggests that AP5 activates alpha v beta 3 by preventing occupation of this calcium site, and that the activated form of alpha v beta 3 differs functionally from the basal form. The active form is more conducive to migration and the basal to tight adhesion.
Highlights
Integrins comprise a large family of heterodimeric cell-surface receptors involved in cell-matrix and cell-cell interactions
We recently showed for the case of ␣IIb3 that the conformational state can affect ligand recognition, but “outsidein” signals as well [20]
We found that a discrete calciumbinding site residing both in ␣v3 and ␣IIb3 was involved in regulating the conformational changes associated with LIBS presentation and activation
Summary
Integrins comprise a large family of heterodimeric cell-surface receptors involved in cell-matrix and cell-cell interactions. That is, they can exist in different conformational states, or activation states, that affect ligand recognition. They can exist in different conformational states, or activation states, that affect ligand recognition Examples of this included ␣IIb3 and some 2 and 1 integrins on leukocytes [13,14,15,16]. We have hypothesized that integrins in general exist on the cell surface as subpopulations in different conformation, or activation, states with specific ligand-binding and signaling functions. Implicit in this hypothesis is the assumption that integrins on constitutively adhered cells can undergo changes in conformation, or activation state, similar to those seen for ␣IIb3. The role of integrin activation in the case of integrins that mediate the conversion from suspension to adhesion in blood cells is obvious, the effect of integrin activation in the context of an adherent cell might be less dramatic
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